! PROJECT SUMMARY Newborn screening (NBS) has been an integral part of preventable health care since the 1960?s. In recent years, new screening technologies have led to a remarkable expansion of the numbers and types of disorders on NBS panels. For each new disorder under consideration, we are faced with the need to evaluate and optimize screening methodology and accuracy, and to objectively analyze the clinical benefit and potential risks of screening. Pilot NBS are an ideal way to gather this essential information and is recognized as such by Public Law 113-240 Sec 116 of the Newborn Screening Saves Lives Reauthorization Act of 2014, which encouraged the NIH to ?conduct pilot studies on conditions recommended by the Advisory Committee to ensure that screenings are ready for nationwide implementation.? In our first funding cycle, we conducted a highly productive pilot NBS for lysosomal storage disorders (LSDs) in conjunction with the renowned New York State NBS Program. We have demonstrated that our pilot screen infrastructure is a robust, efficient, and cost- effective program that is easily conducive to expansion and modification. Thus, in this proposal we will capitalize on our experience to create ?NY ScreenPlus,? a fully comprehensive, fluid, pilot NBS program that will screen consented infants for specific disorders that are under consideration for mass NBS, and then follow screen positive children over time to gather crucial data about the impact of NBS on outcome. Our initial pilot panel will include acid sphingomyelinase deficiency, cerebrotendinous xanthomatosis, ceroid lipofuscinosis type 2, Gaucher disease, Fabry disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, MPS II, IIIb, IVa, VI, and VII, and Niemann Pick type C. Compared with the first pilot screen, there are several key improvements. NY ScreenPlus will be significantly larger in terms of number of disorders on the panel, geographic area, and number of screened infants. It features a novel cost- and data-sharing model between NIH, several Industry Sponsors, and disease-specific Advocacy groups. Expert Scientific and Community Advisory Boards have been assembled to provide critical oversight and guidance. Lastly, we will work with NBSTRN?s Bioethics and Legal workgroup to utilize our pilot infrastructure to address key ethical, legal, and social issues (ELSI) associated with NBS. Overall, our goals are to 1) determine disease incidence in an ethnically diverse population, 2) define the analytic and clinical validity of the screening tests, 3) use longitudinal clinical, biomarker, radiographic, and biochemical data to gather objective evidence about the impact of NBS on phenotype, and 4) analyze the ELSI associated with screening newborns for complex disorders. In sum, NY ScreenPlus will provide critical, detailed data to help guide objective, ethically sensitive decision-making about NBS. ! !